SUMMARY OF PRODUCT CHARACTERISTICS. for. Galliapharm, radionuclide generator

Transcription

1 Date 15 September 2014 SUMMARY OF PRODUCT CHARACTERISTICS for Galliapharm, radionuclide generator This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Galliapharm 2. QUALITATIVE AND QUANTITATIVE COMPOSITION The radionuclide generator contains germanium ( 68 Ge) chloride as mother nuclide which decays to the daughter nuclide gallium ( 68 Ga) chloride. The germanium ( 68 Ge) used for the production of the 68 Ge/ 68 Ga-generator is carrier-free. The Galliapharm radionuclide generator is a system for the elution of gallium ( 68 Ga) chloride solution for radiolabelling Ph. Eur. This solution is eluted from a TiO 2 column on which the mother nuclide germanium ( 68 Ge) chloride, parent of gallium ( 68 Ga) chloride is fixed. The system is shielded. Physical characteristics of both mother and daughter are summarized in Table 1. Table 1: physical characteristics of 68 Ge and 68 Ga Physical characteristics of 68 Ge 68 Ga Half-live days minutes Type of decay Electron capture Positron emission X-rays (13.1 %) (25.7 %) (1.64 %) (3.2 %) (0.03 %) (1.37 %) (2.69 %) 9.57 (0.55 %) gammas 511 kev ( %), kev (0.03 %) kev (0.09 %), kev (3.22 %) kev (0.09 %) kev (0.14 %) Galliapharm,+radionuclide+generator.docx Page 1 of 23

2 beta+ Energy max. Energy kev kev (1.20 %) kev kev (87.94 %) Data derived from nudat ( The quantity of gallium ( 68 Ga) chloride solution for radiolabelling Ph. Eur. that may be eluted from the generator is dependent on the quantity of germanium ( 68 Ge) chloride present, the volume of eluent used (typically 5 ml) and the lapsed time since the previous elution. If mother nuclide and daughter nuclide are in equilibrium more than 60 % of the present gallium ( 68 Ga) chloride can be eluted. Table 2 summarizes the activity on the generator and obtained by elution at the start of the shelf-life and at the end of the shelf-life. Table 2: activity on the generator and obtained by elution Strength Activity inside generator at the start of shelf-life Activity inside generator at the end of shelf-life Eluted activity at the start of shelf-life* Eluted activity at the end of shelflife* 0.74 GBq 0.74 GBq ± 10 % 0.3 GBq ± 10 % NLT 0.45 GBq NLT 0.18 GBq 1.11 GBq 1.11 GBq ± 10 % 0.4 GBq ± 10 % NLT 0.67 GBq NLT 0.24 GBq 1.48 GBq 1.48 GBq ± 10 % 0.6 GBq ± 10 % NLT 0.89 GBq NLT 0.36 GBq 1.85 GBq 1.85 GBq ± 10 % 0.7 GBq ± 10 % NLT 1.11 GBq NLT 0.42 GBq NLT = not less than * in equilibrium More detailed explanations and examples for elutable activities at various time points are given in section 12. For the full list of excipients, see section PHARMACEUTICAL FORM Radionuclide generator The generator is presented as a stainless steel case with two handles and an inlet and an outlet port. The solution for elution is attached to the inlet port whereas the eluate can be collected at the outlet port or inserted directly into a synthesis apparatus. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications This medicinal product is not intended for direct use in patients. The eluate (gallium ( 68 Ga) chloride solution) is used for in vitro radiolabelling of specific carrier molecules which have been specifically developed and authorised for radiolabelling with this radionuclide to be used for diagnostic imaging with positron emission tomography (PET). Galliapharm,+radionuclide+generator.docx Page 2 of 23

3 4.2 Posology and method of administration This medicinal product is for use in designated nuclear medicine facilities only, and should only be handled by specialists experienced with in vitro radiolabelling. Posology The quantity of the eluate (gallium ( 68 Ga) chloride solution) required for radiolabelling and the quantity of 68 Ga-labelled medicinal product that is subsequently administered will depend on the medicinal product that is radiolabelled and its intended use. Refer to the Summary of Product Characteristics/package leaflet of the particular medicinal product to be radiolabelled. Paediatric population Please refer to the Summary of Product Characteristics/package leaflet of the 68 Ga-labelled medicinal product for more information concerning its paediatric use. Method of administration The gallium ( 68 Ga) chloride solution is not intended for direct use in patients but is used for in vitro radiolabelling of various carrier molecules. The route of administration of the final medicinal product should be adhered to. For instructions on extemporary preparation of the medicinal product before administration, see section Contraindications Do not administer gallium ( 68 Ga) chloride solution directly to the patient. The use of 68 Ga-labelled medicinal products is contraindicated in the following case: - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. For information on contraindications to particular 68 Ga-labelled medicinal products prepared by radiolabelling with gallium ( 68 Ga) chloride solution, refer to the Summary of Product Characteristics/package leaflet of the particular medicinal product to be radiolabelled. 4.4 Special warnings and precautions for use Gallium ( 68 Ga) chloride solution is not to be administered directly to the patient but is used for in vitro radiolabelling of various carrier molecules. For each patient, the radiation exposure must be justifiable by the likely benefit. The activity administered should in every case be as low as reasonably achievable to obtain the required effect. General warnings For information concerning special warnings and special precautions for use of 68 Galabelled medicinal products refer to the Summary of Product Characteristics/package leaflet of the medicinal product to be radiolabelled. Galliapharm,+radionuclide+generator.docx Page 3 of 23

4 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies of gallium ( 68 Ga) chloride with other medicinal products have been performed, because gallium ( 68 Ga) chloride is a precursor solution for radiolabelling of medicinal products. For information concerning interactions associated with the use of 68 Ga-labelled medicinal products refer to the Summary of Product Characteristics/package leaflet of the medicinal product to be radiolabelled. 4.6 Pregnancy and lactation Women of childbearing potential When an administration of radioactive medicinal products to a woman of childbearing potential is intended, it is important to determine whether or not she is pregnant. Any woman who has missed a period should be assumed to be pregnant until proven otherwise. If in doubt about her potential pregnancy (if the woman has missed a period, if the period is very irregular etc.), alternative techniques not using ionising radiation (if there are any) should be offered to the patient. Pregnancy Radionuclide procedures carried out on pregnant women also involve radiation dose to the foetus. Only essential investigations should therefore be carried out during pregnancy, when the likely benefit far exceeds the risk incurred by the mother and foetus. Breast-feeding Before administering a radioactive medicinal product to a mother who is breast-feeding, consideration should be given to whether the investigation could be reasonably delayed until the mother has ceased breast-feeding. If the administration is considered necessary, breast-feeding should be interrupted and the expressed feeds discarded. Further information concerning the use of a 68 Ga-labelled medicinal product in pregnancy and breast-feeding is specified in the Summary of Product Characteristics/package leaflet of the medicinal product to be radiolabelled. Fertility Further information concerning the use of a 68 Ga-labelled medicinal product concerning fertility is specified in the Summary of Product Characteristics/package leaflet of the medicinal product to be radiolabelled. 4.7 Effects on ability to drive and use machines Effects on ability to drive and use machines following administration of 68 Ga-labelled medicinal products will be specified in the Summary of Product Characteristics/package leaflet of the medicinal product to be radiolabelled. 4.8 Undesirable effects Possible adverse reactions following the use of a 68 Ga-labelled medicinal product, will be dependent on the specific medicinal product being used. Such information will be supplied in the Summary of product Characteristics/package leaflet of the medicinal product to be radiolabelled. Galliapharm,+radionuclide+generator.docx Page 4 of 23

5 Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Sundhedsstyrelsen Axel Heides Gade 1 DK-2300 København S Website: sst@sst.dk 4.9 Overdose Accidental administration of the eluate consisting of 0.1 mol/l hydrochloric acid may cause local venous irritation and, in case of paravenous injection, tissue necrosis. The catheter or affected area should be irrigated with isotonic saline solution. No toxic effects are to be expected from the free 68 Ga after an inadvertent administration of the eluate. The administered free 68 Ga decays almost completely to inactive 68 Zn within a short time (97 % are decayed in 6 hours). During this time, 68 Ga is mainly concentrated in the blood/plasma (bound to transferrin) and in the urine. The patient should be hydrated to increase the excretion of the 68 Ga and forced diuresis as well as frequent bladder voiding is recommended. Human radiation dose may be estimated using the information given in section PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Other diagnostic radiopharmaceuticals, ATC code: V09X The pharmacodynamic properties of 68 Ga-labelled medicinal products prepared by radiolabelling with Galliapharm prior to administration will be dependent on the nature of the medicinal product to be labelled. Refer to the Summary of Product Characteristics/package leaflet of the product to be radiolabelled. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Galliapharm in all subsets of the paediatric population on grounds of lack of significant therapeutic benefit over existing treatments (see section 4.2 for information on paediatric use). This waiver does however not extend to any diagnostic or therapeutic uses of the product when linked to a carrier molecule. 5.2 Pharmacokinetic properties Gallium ( 68 Ga) chloride solution is not intended for direct use in patients but is used for in vitro radiolabelling of various carrier compounds. Therefore, the pharmacokinetic properties of 68 Ga-labelled medicinal products will depend on the nature of the medicinal product to be radiolabelled. Although gallium ( 68 Ga) chloride solution is not intended for direct use in patients, its pharmacokinetic properties were investigated in rats. Galliapharm,+radionuclide+generator.docx Page 5 of 23

6 5.3 Preclinical safety data The toxicological properties of 68 Ga labelled medicinal products prepared by radiolabelling with gallium ( 68 Ga) chloride solution, prior to administration, will depend on the nature of the medicinal product to be radiolabelled. 5 ml of the Galliapharm eluate contains a potential maximum of 1850 MBq 68 Ga and 18.5 kbq 68 Ge (0.001 % breakthrough). This corresponds to 1.2 ng gallium and 0.07 ng germanium. Toxicological studies have demonstrated that with a single intravenous injection of mg Ga/kg in rats or mg Ga/kg in rabbits, administered as gallium lactate, no deaths were observed. The dose at which no toxicity occurs after repeated administration has not been determined, but the LD 50 is 67.5 mg Ga/kg in rats and 80 mg Ga/kg in mice with daily dosing of gallium nitrate for 10 days. This medicinal product is not intended for regular or continuous administration. A study on the pharmacokinetic properties performed in rats has shown that following intravenous administration in rats, gallium ( 68 Ga) chloride is slowly cleared from the blood with a biological half-life of 188 h in male and 254 h in female rats. This is because free Ga 3+ behaves in a similar way as Fe 3+. However as the biological half-life is much longer than the physical half-life of 68 Ga (67.71 min) at 188 h or 254 h almost all 68 Ga has already decayed to inactive 68 Zn. For example, in 6 h approx. 97 % of the initial 68 Ga has decayed. 68 Ga is excreted predominantly into the urine, with some retention in the liver and kidneys. The organs with the highest 68 Ga radioactivity, other than blood, plasma and urine, are the liver (1.5% of the injected amount per gram in female rats and 0.8% IA/g in male rats after 60 min) and the lungs, spleen and bone ( % IA/g in female rats and 0.5% IA/g in male rats after 60 min). In female rats, the 68 Ga radioactivity in female genital organ, i.e. uterus and ovaries, is comparable to that seen in the lungs ( % IA/g). In male rats, the 68 Ga radioactivity in the testes is very low ( 2% IA/g at any time). The radioactivity resulting from 68 Ge breakthrough is extremely low in rats, with the highest 68 Ge radioactivity seen in the urine and liver ( 2x 10-4 % of the injected dose per gram, 5 min to 3 h after injection). Extrapolating from the female and male rat 68 Ga data, the estimated effective dose for a 57 kg woman is msv/mbq and for a 70 kg man msv/mbq. No teratogenic effects or major maternal toxicity were seen in hamsters administrated 30 mg Ga or 40 mg Ge per kg intravenously on day 8 of gestation. The mutagenic or carcinogenic potential has not been investigated for this product. Overall, effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. Galliapharm,+radionuclide+generator.docx Page 6 of 23

7 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Matrix: Titanium dioxide. Bag of solution for elution: Sterile ultrapure 0.1 mol/l hydrochloric acid. 6.2 Incompatibilities Radiolabelling of carrier molecules with gallium ( 68 Ga) chloride is very sensitive to the presence of trace metal impurities. It is important that all glassware, syringe needles etc., used for the preparation of the radiolabelled medicinal product are thoroughly cleaned to ensure freedom from such trace metal impurities. Only syringe needles (for example, non-metallic) with proven resistance to dilute acid should be used to minimise trace metal impurity levels. It is recommended not to use uncoated chlorobutyl stoppers for the elution vial as they may contain considerable amounts of zinc that is extracted by the acidic eluate. 6.3 Shelf life Radionuclide generator: 12 months from calibration date. The calibration date and the expiry date are stated on the label. Gallium ( 68 Ga) chloride eluate: After elution, immediately use the eluate. 6.4 Special precautions for storage Radionuclide generator: Do not store above 25 C. Storage of radiopharmaceuticals should be in accordance with national regulations on radioactive materials. 6.5 Nature and contents of container The glass column consists of a borosilicate glass tube (Ph. Eur. type I) and PEEK (Polyetheretherketone) end plugs which are attached to PEEK inlet and outlet lines via HPLC-style fingertight fittings. These lines are connected to two unions that pass through the outer case of the Galliapharm generator. The column is contained within the lead shield assembly. The shield assembly is secured in a stainless steel outer box with two handles. Accessories supplied with the generator: 1 PP - bag with 250 ml sterile ultrapure 0.1 mol/l hydrochloric acid 2 x Adapter 1/16 to male LUER (PEEK) 2 x Tubing (60 cm) (PEEK) 3 x Finger tight fitting 1/ (PEEK) 1 x Finger tight fitting 1/16 M6 (PEEK) 1 x Stopcock manifold (TPX/HDPE) 1 x Vented spike (ABS/PE) Galliapharm,+radionuclide+generator.docx Page 7 of 23

8 Pack sizes: The radionuclide generators are supplied with the following 68 Ge activity amounts at calibration date: 0.74 GBq, 1.11 GBq, 1.48 GBq, 1.85 GBq. Galliapharm,+radionuclide+generator.docx Page 8 of 23

9 Sectional view of the Galliapharm radionuclide generator Handle Stainless steel case Inlet port Lead shielding Outlet port Fluid lines Front plate with inlet and outlet ports TiO 2 column Galliapharm,+radionuclide+generator.docx Page 9 of 23

10 Front view of the Galliapharm radionuclide generator Handles Inlet port Stainless steel case Outlet port Front plate with inlet and outlet ports Size: 230 mm x 132 mm x 133 mm (H x W x D) Weight: approximately 14 kg Galliapharm,+radionuclide+generator.docx Page 10 of 23

11 6.6 Special precautions for disposal and other handling General warnings Radiopharmaceuticals should be received, used and administered only by authorised persons in designated clinical settings. Their receipt, storage, use, transfer and disposal are subject to the regulations and/or appropriate licenses of the competent official organisation. Radiopharmaceuticals should be prepared in a manner which satisfies both radiation safety and pharmaceutical quality requirements. Appropriate aseptic precautions should be taken. The generator must not be disassembled for any reason as this may damage the internal components and possibly lead to a leak of radioactive material. Also, disassembly of the stainless steel casing will expose the lead shielding to the operator. Administration procedures should be carried out in a way to minimize risk of contamination of the medicinal product and irradiation of the operators. Adequate shielding is mandatory. The administration of radiopharmaceuticals creates risks for other persons from external radiation or contamination from spill of urine, vomiting, etc. Radiation protection precautions in accordance with national regulations must therefore be taken. The residual activity of the generator must be estimated before disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Eckert & Ziegler Radiopharma GmbH Robert-Rössle-Str Berlin Germany 8. MARKETING AUTHORISATION NUMBER(S) DATE OF FIRST AUTHORISATION 15 September DATE OF REVISION OF THE TEXT DOSIMETRY The radiation dose received by the various organs following intravenous administration of a 68 Ga-labelled medicinal product is dependent on the specific medicinal product being radiolabelled. Information on radiation dosimetry of each different medicinal product following administration of the radiolabelled preparation will be available in the Summary of Product Characteristics of the particular medicinal product. Galliapharm,+radionuclide+generator.docx Page 11 of 23

12 The dosimetry tables below are presented in order to evaluate the contribution of nonconjugated 68 Ga to the radiation dose following the administration of 68 Ga-labelled medicinal product or resulting from an accidental intravenous injection of gallium ( 68 Ga) chloride solution. The dosimetry estimates were based on a rat distribution study and the calculations were effected using OLINDA - Organ Level INternal Dose Assessment Code. Time points for measurements were 5 minutes, 30 minutes, 60 minutes, 120 minutes and 180 minutes. Table 3: Absorbed dose per unit activity administered - women Absorbed dose per unit radioactivity administered (msv/mbq) Organ Adult (57 kg) 15 years (50 kg) 10 years (30 kg) 5 years (17 kg) 1 year (10 kg) Newborn (5 kg) Adrenals Brain Breasts Gallbladder Wall LLI Wall Small Intestine Stomach Wall ULI Wall Heart Wall Kidneys Liver Lungs Muscle Ovaries Pancreas Red Marrow Osteogenic Cells Skin Spleen Thymus Thyroid Urinary Bladder Wall Uterus Total Body Effective Dose (msv/mbq) Galliapharm,+radionuclide+generator.docx Page 12 of 23

13 Table 4: Absorbed dose per unit activity administered men Absorbed dose per unit radioactivity administered (msv/mbq) Organ Adult (70 kg) 15 years (50 kg) 10 years (30 kg) 5 years (17 kg) 1 year (10 kg) Newborn (5 kg) Adrenals Brain Breasts Gallbladder Wall LLI Wall Small Intestine Stomach Wall ULI Wall Heart Wall Kidneys Liver Lungs Muscle Pancreas Red Marrow Osteogenic Cells Skin Spleen Testes Thymus Thyroid Urinary Bladder Wall Total Body Effective Dose (msv/mbq) For this product, the effective dose resulting from an accidental intravenously injected activity of 250 MBq is 12.1 msv for a 57-kg female adult and 8.45 msv for a 70-kg male adult. Literature data on the radiation dose to patients of 68 gallium citrate can be seen in the table 5 below and may be used to estimate distribution after inadvertent application of unbound 68 gallium from the generator eluate, even though the data were obtained using a different salt. Galliapharm,+radionuclide+generator.docx Page 13 of 23

14 Table 5: Absorbed dose per unit activity administered of 68 Ga-Citrate (ICRP 53) Absorbed dose per unit radioactivity administered of 68 Ga-Citrate (msv/mbq) Organ Adult 15 years 10 years 5 years 1 year Adrenals Bone surface Breast LLI Wall Small Intestine Stomach Wall ULI Wall Kidneys Liver Lungs Pancreas Red Marrow Spleen Testes Thyroid Urinary Bladder Wall Other tissue Effective Dose (msv/mbq) External radiation exposure The average surface or contact radiation for the Galliapharm radionuclide generator is less than 0.14 µsv/h per MBq of 68 Ge. For example, a 1.85 GBq generator will reach a maximum surface dose rate of 260 µsv/h. It is generally recommended that the generator is stored within auxiliary shielding to minimize dose to operating personnel. 12. INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS Elution of the generator must be performed in premises complying with the national regulations concerning the safety of use of radioactive products. Unpacking of the generator 1. Check outer box for shipping damage. If damaged, perform radiation wipe survey of the damaged area. If counts exceed 40 counts per second per 100 cm 2 notify your Radiation Safety Officer. 2. Cut security tape on top of shipping carton. Remove the inner foam support from the cardboard box. Separate the foam halves carefully. 3. Carefully remove generator. Perform radiation survey. CAUTION: Drop hazard: The Galliapharm generator weighs approximately 14 kg. Handle with care to avoid potential injuries. If generator is dropped or if shipping damage extends into the inner box, check for leaks and perform a wipe survey of the generator. Also check Galliapharm,+radionuclide+generator.docx Page 14 of 23

15 for internal damage by slowly tilting the generator 90. Listen for broken/loose parts. 4. Perform wipe survey of box inserts and generator outer surface. If wipes exceed 40 counts per second per 100 cm 2, notify your Radiation Safety Officer. 5. Check sealed inlet and outlet ports for damage. Do not remove the port plugs before the elution lines are prepared and ready for installation. Optimal positioning: 1. When installing the Galliapharm radionuclide generator in its final position, i.e. with a synthesis device or for manual elutions, it is recommended to keep the outlet line as short as possible as the length of this tubing may influence the recovered yield in the receiving/reaction vial. 2. Use auxiliary shielding when positioning the Galliapharm generator. Preparation: 1. Accessories supplied with the generator: 1 PP - bag with 250 ml sterile ultrapure 0.1 mol/l hydrochloric acid 2 x Adapter 1/16 to male LUER (PEEK) 2 x Tubing (60 cm) (PEEK) 3 x Fingertight fitting 1/ (PEEK) for outlet port and adapters 1 x Fingertight fitting 1/16 M6 (PEEK) for inlet port 1 x Stopcock manifold (TPX/HDPE) 1 x Vented spike (ABS/PE) Wear gloves to assemble the lines and connect the eluent solution to the generator. 2. Inlet port and line: Please note: the inlet port has a customized thread to avoid misconnection. Only the special fingertight fitting 1/16 M6 will fit into this port. For assembling the inlet line connect the vented spike to one side of the stopcock manifold. On the other side of the stopcock manifold connect the 1/16 to male LUER adapter. Attach the PEEK tubing with 1/ fingertight fitting. Cut the PEEK line to desired length. Prepare the special 1/16 M6 fingertight fitting, but do not connect yet. 3. Outlet port and line: For assembling the outlet line attach the second PEEK line to the second 1/16 to LUER adapter using the 1/ fingertight fitting. Prepare the third 1/ fingertight fitting, but do not connect yet. Picture of assembled elution accessories before connected to the Galliapharm generator Galliapharm,+radionuclide+generator.docx Page 15 of 23

16 4. Hang the PP - bag with the 250 ml sterile ultrapure 0.1 N hydrochloric acid close to the inlet port but above the Galliapharm generator. 5. Turn the valves at the stopcock manifold in the appropriate direction that no liquid can enter through the spike. Push spike into the PP bag connection; then slowly remove all air from the stopcock valves and the attached inlet line and fill with sterile ultrapure 0.1 mol/l hydrochloric acid. When manifold and line are filled, close valves to stop flow. 6. Remove the plug from inlet port and connect inlet line with the special 1/16 M6 fingertight fitting. Avoid hard bending or pinching of the line. 7. Remove plug from outlet port and connect prepared outlet line with the 1/ fingertight fitting. Avoid hard bending or pinching of the line. 8. The Galliapharm generator is now ready for the first elution. The generator is designed not to drain itself, when accidently ports are left open, but it is necessary to take care about the inlet and outlet lines and also about the positions of the stopcock valves.. First elution: 1. When installing the Galliapharm radionuclide generator in its final position, i.e. with a synthesis device or for manual elutions, it is recommended to keep the outlet line as short as possible as the length of this tubing may influence the recovered yield in the receiving/reaction vial. 2. Prepare additional necessary materials: Personal protective equipment: elutions should be performed while wearing eye and hand protection and also appropriate laboratory cloth. Sterile syringe with 10 ml volume. Shielded receiving vial or vessel with 10 ml or larger volume. Avoid uncoated chlorobutyl stoppers as they may contain considerable amounts of zinc that is extracted by the acidic eluate. 3. Aseptic working technique must be maintained during the assembly process, especially when handling the ports. This is critical for the maintenance of sterility. Galliapharm,+radionuclide+generator.docx Page 16 of 23

17 4. Attach the syringe to a port of the stopcock manifold and fill with 10 ml of sterile ultrapure 0.1 N hydrochloric acid from the PP - bag, but avoid any air inside the syringe. 5. Connect the vial or other receiving vessel to the outlet line using the appropriate connector. The vessel must have sufficient capacity to accept the eluate volume. 6. Turn valve of stopcock manifold towards the inlet port of the generator. Introduce the 10 ml sterile ultrapure 0.1 mol/l HCI at a rate no greater than 2 ml/minute. Eluting at a faster rate may reduce the life of the generator. 5 ml of eluent will fully elute the generator, but for the first elution it is recommended to use 10 ml. If high resistance is encountered, do not force solution into generator. If a peristaltic pump is used for elution it should be set to a volume rate of not more than 2 ml/minute. The user should also verify that eluent is flowing without unusual resistance. If high resistance is noted, discontinue elution. Caution: Be sure to introduce eluent through the inlet port; do not elute the Galliapharm generator in reverse direction. Elution efficiency ( 68 Ga yield) may be reduced if air is introduced to the generator column. 7. Collect eluate in shielded receiving vessel and measure solution with a calibrated dose calibrator to determine the yield. If less than 5 ml of eluate has been collected, measurement may not represent the total potential yield of generator. Please decay correct the measured activity to the starting time of the elution. For optimal yield of the generator in its final position it is recommended to determine the elution peak by collecting small fractions of 0.5 ml. 8. It is recommended to discard the first eluate due to the potential 68 Ge breakthrough in this eluate. 9. It is recommended to test the eluate for 68 Ge breakthrough after the first elutions by comparing the activity level of the 68 Ga and the 68 Ge. For further details please refer to Ph. Eur. monograph Continuous routine elution: 1. Repeat the steps of the first elution but use only 5 ml for the continuous routine elution. The Galliapharm is designed to elute all of the available 68 Ga activity in a volume of 5 ml. 2. Elute the Galliapharm radionuclide generator at every working day with 5 ml sterile ultrapure 0.1 mol/l hydrochloric acid. 3. The solution eluted is a clear, sterile and colourless gallium ( 68 Ga) chloride solution, with a ph between 0.5 and 2.0 and a radiochemical purity greater than 95 %. Check the clarity of the eluate before use and discard it if the solution is not clear. 4. If the generator has not been used for a period of 3 days or more free 68 Ge ions Galliapharm,+radionuclide+generator.docx Page 17 of 23

18 accumulate within the column over time. Therefore it is recommended that the column is eluted once at least 7-24 hours prior to eluting for labelling. This elution should be done using 10 ml of sterile ultrapure 0.1 N hydrochloric acid to fully wash the impurities from the column. 5. It is recommended to test the eluate for 68 Ge breakthrough during routine elutions by comparing the activity level of the 68 Ga and the 68 Ge. For further details please refer to Ph. Eur. monograph Caution: If fluid leaks are observed at any time, immediately stop eluting and attempt to contain the leaking fluid. The 68 Ge/ 68 Ga-generator is supplied with 250 ml of sterile ultrapure 0.1 mol/l hydrochloric acid. This amount is usually sufficient for at least 40 elutions. The 68 Ge/ 68 Ga-generator should only be eluted with sterile ultrapure 0.1 mol/l hydrochloric acid supplied by the marketing authorization holder. Additional bags may be purchased as consumables from the marketing authorisation holder. Exchange of sterile ultrapure 0.1 mol/l hydrochloric acid bag 1. When the sterile ultrapure 0.1 mol/l hydrochloric acid is almost consumed, it can be replaced by a new sterile ultrapure 0.1 mol/l hydrochloric acid bag. CAUTION: No air should enter the 68 Ge/ 68 Ga-generator. Before disconnecting the empty bag, close all valves at the stopcock manifold that no liquid can enter into the spike. Disconnect the bag from the spike. It is recommended to use a new spike for each sterile ultrapure 0.1 mol/l hydrochloric acid bag. 2. Aseptic technique is critical for maintenance of sterility and must be used during the exchange procedure. 3. Hang the new PP - bag with the 250 ml sterile ultrapure 0.1 mol/l hydrochloric acid close to the inlet port but above the Galliapharm generator. 4. Push the spike into the PP bag connection; carefully check for air bubbles and slowly remove all air from the stopcock valves and the attached inlet line by turning the valves in the right position. Entering of air into the 68 Ge/ 68 Ga-generator should be avoided. 5. When manifold and line are filled, close valves to stop flow. The generator is now ready for further use. Galliapharm elution yield The activity stated on the label of the Galliapharm generator is expressed in 68 Ge available at the calibration date (12:00 CET). The available 68 Ga activity depends on the 68 Ge activity at the time of elution and the elapsed time since the previous elution. A Galliapharm generator in full equilibrium yields more than 60 % of 68 Ga using an Galliapharm,+radionuclide+generator.docx Page 18 of 23

19 elution volume of 5 ml sterile ultrapure 0.1 mol/l hydrochloric acid. The output will decrease with decay of the 68 Ge parent over time. For example, after 9 months' decay (39 weeks), the 68 Ge will be reduced by 50 % (see Table 6). Table 6: Decay Chart for 68 Ge Elapsed Time Decay Factor Elapsed Time Decay Factor in weeks in weeks After an elution of the Galliapharm generator the 68 Ga will be build up by the continuous decay of the parent 68 Ge. The generator requires at least 7 hours to achieve almost full yield after being eluted, but in practice it is also possible to elute the generator after 4 hours. Table 7 shows the build-up factor of activity of 68 Ga which can be eluted after times varying from 0 to 410 minutes since the previous elution: Galliapharm,+radionuclide+generator.docx Page 19 of 23

20 Table 7: Build-up factors of 68 Ga Elapsed Time in minutes Build-Up Factor Elapsed Time in minutes Build-Up Factor Examples A 1.85 GBq generator is 12 weeks old. According to table 6, the activity of 68 Ge on the column can be calculated as follows: 1.85 GBq x 0.81 = GBq In full equilibrium the activity of 68 Ga on the column is also GBq. The generator is eluted and the collected 68 Ga activity is GBq which corresponds to a typical yield of 70 %. The same generator is eluted 4 hours later. The 7 hours needed to reach the 68 Ge / 68 Gaequilibrium have not elapsed and the 68 Ga activity build up on the column can be calculated according to table 7 as follows: GBq x 0.91 = GBq With a typical yield of 70 % 68 Ga, the collected activity would be: Galliapharm,+radionuclide+generator.docx Page 20 of 23

21 1.364 GBq x 0.70 = 955 MBq Note: The activity of 68 Ga in the eluate can be measured to check the quality with regard to identity and content. The activity should be measured immediately after elution, but may also be measured up to 5 half-life periods after elution. Due to the short half-time of 68 Ga which is minutes, the elapsed time between the elution and the measurement of the activity has to be decay corrected to determine the actual yield at the elution time with the decay chart of 68 Ga, table 8. Example A new 1.85 GBq generator is eluted. The activity of 68 Ga measured 10 minutes after the elution was GBq. The yield at the time of the elution can be obtained by dividing the measured activity by the corresponding factor of the elapsed time stated in table 8: GBq / = GBq This corresponds to a yield of 68 Ga of 70 % at the time of the elution: GBq / 1.85 GBq x 100 % = 70 % Galliapharm,+radionuclide+generator.docx Page 21 of 23

22 Table 8: Decay chart of 68 Ga Elapsed Time Decay Factor Elapsed Time Decay Factor in minutes in minutes Galliapharm,+radionuclide+generator.docx Page 22 of 23

23 Quality control Clarity of the solution, ph and the radioactivity must be checked before radiolabelling. 68 Ge breakthrough A small amount of 68 Ge is washed from the column with each elution. 68 Ge breakthrough is expressed as a percentage of total 68 Ga eluted from the column, corrected for decay. The 68 Ge breakthrough is not more than % of the eluted 68 Ga activity. The breakthrough for this generator typically begins as low as % at the point of release and may rise slightly with the number of elutions. To keep the breakthrough low, the generator should be eluted at least once per working day. When used according to these instructions, the breakthrough should stay below % for 12 months. For testing the 68 Ge breakthrough the activity level of the 68 Ga and the 68 Ge in the eluate should be compared. For further details please refer to Ph. Eur. monograph Warning: Breakthrough of 68 Ge can increase above % if the generator is not eluted for more than 2 days. If the generator has not been used for 3 days or more, it should be pre-eluted with 10 ml of sterile ultrapure 0.1 mol/l hydrochloric acid 7-24 hours prior to the intended use. The shelf-life of this generator has been evaluated by eluting every working day with 5 ml of sterile ultrapure 0.1 mol/l hydrochloric acid. The use of other volumes or qualities of the eluent is the responsibility of the end-user. Galliapharm,+radionuclide+generator.docx Page 23 of 23